Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management.
Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management.
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DOI：
10.1001/jamaneurol.2014.3065
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发表时间：
2015-01
期刊：
影响因子：
29
通讯作者：
Putzki N
中科院分区：
文献类型：
--
作者：
Arvin AM;Wolinsky JS;Kappos L;Morris MI;Reder AT;Tornatore C;Gershon A;Gershon M;Levin MJ;Bezuidenhoudt M;Putzki N
水痘-带状疱疹病毒（VZV）感染在多发性硬化症（MS）患者中的报道越来越多，并构成了一个值得关注的领域，特别是随着更多影响t细胞介导免疫的MS疾病修饰治疗的出现。评估芬高利莫治疗患者VZV感染的发生率、危险因素和临床特征，并为预防和管理提供建议。芬戈莫德临床试验中VZV感染率基于已完成的对照2期和3期研究（3916名受试者）和正在进行的非对照扩展期（3553名受试者）的汇总数据。年龄在18 - 55岁（2期研究为18 - 60岁）且诊断为复发-缓解型MS的男性和女性患者有资格参加这些研究。在上市后环境中，评估了2010年以来的报告率。在临床试验中，患者接受剂量为0.5或1.25 mg/d的fingolimod、干扰素β -1a或安慰剂。在上市后的环境中，所有患者都接受了芬戈莫德，0.5 mg/d（分析时的总暴露量为54,000患者-年）。计算每1000患者年的VZV感染发生率是基于试验中不良事件的报告和上市后的环境。总体而言，在临床试验中，与安慰剂相比，芬戈莫德的VZV感染率较低，但较高（每1000患者年11 vs 6）。正在进行的推广研究也证实了类似的比率。上市后报告的发生率具有可比性（每1000患者年7例），并且随着时间的推移保持稳定。接受芬戈莫德的患者报告带状疱疹感染的比例高于接受其他疾病改善治疗的患者（经验贝叶斯几何平均值，2.57 [90% CI, 2.26-2.91]）；严重带状疱疹感染的比例不高于其他治疗的比例（经验贝叶斯几何平均值为1.88 [90% CI, 0.87-3.70]）。用皮质类固醇治疗复发可能是VZV再激活的危险因素。在临床试验中，芬戈莫德（0.5 mg/d）组的VZV感染率较低，但高于安慰剂组。上市后报告的比率具有可比性。我们没有发现暴露时间越长，风险越积累的迹象。严重或复杂的带状疱疹病例并不常见。我们建议在对原发VZV感染易感的患者开始芬戈莫德治疗和免疫接种之前，确定患者的VZV免疫状态。常规抗病毒预防不需要，但同时使用脉冲皮质类固醇治疗超过3 - 5天需要进行个体风险-收益评估。警惕识别早期VZV症状对于及时进行抗病毒治疗非常重要。
Varicella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity. To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management. Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18–60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated. In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54 000 patient-years at the time of analysis). Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting. Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26–2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87–3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation. Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient’s VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.